Background The use of technologies has served to reduce gaps in access to treatment, and digital health interventions show promise in the care of mental health problems. However, to understand what and how these interventions work, it is imperative to document the aspects related to their challenging implementation. Objective The aim of this study was to determine what evidence is available for synchronous digital mental health implementation and to develop a framework, informed by a realist review, to explain what makes digital mental health interventions work for people with mental health problems. Methods The SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, and Research type) framework was used to develop the following review question: What makes digital mental health interventions with a synchronous component work on people with mental health problems, including depression, anxiety, or stress, based on implementation, economic, quantitative, qualitative, and mixed methods studies? The MEDLINE, EBM Reviews, PsycINFO, EMBASE, SCOPUS, CINAHL Complete, and Web of Science databases were searched from January 1, 2015, to September 2020 with no language restriction. A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR-2) was used to assess the risk of bias and Confidence in Evidence from Reviews of Qualitative Research (CERQual) was used to assess the confidence in cumulative evidence. Realist synthesis analysis allowed for developing a framework on the implementation of synchronous digital mental health using a grounded-theory approach with an emergent approach. Results A total of 21 systematic reviews were included in the study. Among these, 90% (n=19) presented a critically low confidence level as assessed with AMSTAR-2. The realist synthesis allowed for the development of three hypotheses to identify the context and mechanisms in which these interventions achieve these outcomes: (1) these interventions reach populations otherwise unable to have access because they do not require the physical presence of the therapist nor the patient, thereby tackling geographic barriers posed by in-person therapy; (2) these interventions reach populations otherwise unable to have access because they can be successfully delivered by nonspecialists, which makes them more cost-effective to implement in health services; and (3) these interventions are acceptable and show good results in satisfaction because they require less need of disclosure and provide more privacy, comfortability, and participation, enabling the establishment of rapport with the therapist. Conclusions We developed a framework with three hypotheses that explain what makes digital mental health interventions with a synchronous component work on people with mental health problems. Each hypothesis represents essential outcomes in the implementation process. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42020203811; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020203811 International Registered Report Identifier (IRRID) RR2-10.12688/f1000research.27150.2